Liver cancer is the third most common cause of cancer mortality, with approximately 500,000 to 1 million annual deaths worldwide [1]. The American Cancer Society estimated that about 24,000 new cases of liver cancer occurred in the US in 2010, with more than 80% of these being hepatocellular carcinoma (HCC). An estimated 19,000 deaths in the US in 2010 resulted from liver cancer. The incidence and death rates for liver cancer have continued to increase since the early 1980s.
To date, surgical resection is considered the best treatment for liver cancer, but only a small proportion of patients qualify for surgery and there is a high rate of recurrence [2]. Many patients with HCC do not receive any therapy. Liver transplantation has been successful in treating limited-stage HCC. Only a minority of patients with HCC, however, qualifies for transplantation. Standard chemotherapy is poorly tolerated in patients who do not qualify for resection. Both doxorubicin and cisplatin are frequently used, but overall response rates are low, and neither prolongs survival substantially. The 5-year survival rate for patients with liver cancer is 14%. Five-year survival is 26% among patients in whom cancer is found at an early stage, compared to only 2% when it is found after spreading to distant organs. It is therefore critical to develop a better understanding of hepatocarcinogenesis at the molecular level to identify novel therapeutic targets that may play a pivotal role in the pathogenesis of this devastating disease.
HCC is the most common tumor that originates in the liver [2]. Recent studies have highlighted the role of various signaling pathways in liver carcinogenesis, including the Wnt/β-catenin pathway, Hedgehog signaling, and receptor tyrosine kinase-related pathways. These discoveries offer potential alternatives for novel targeted therapeutics. In particular, the role of Wnt signaling has been the subject of considerable interest in understanding the molecular pathogenesis of HCC [3]. Aberrant Wnt signaling has been implicated in many types of cancer, including cancers of the colon, skin, brain, liver and prostate[4]. In colorectal carcinomas, abnormal accumulation of β-catenin arises primarily as a result of mutations in β-catenin itself, as well as in APC and axin. These mutations are relatively rare in HCC, however, suggesting that misregulation of the Wnt pathway arises in other ways, including overexpression of other components of the pathway, such as Wnt ligands and Fzd receptors [3]. To date, however, it is not known which ligands or receptors are responsible for activation of the β-catenin pathway in HCC.